A Photoactivatable Platinum(IV) Anticancer Complex Conjugated to the RNA Ligand Guanidinoneomycin

Evyenia Shaili, Marta Fernández-Giménez, Savina Rodríguez-Astor, Albert Gandioso, Lluís Sandín, Carlos García-Vélez, Anna Massaguer, Guy J. Clarkson, Julie A. Woods, Peter J. Sadler (Lead / Corresponding author), Vicente Marchán (Lead / Corresponding author)

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    Abstract

    A photoactivatable platinum(IV) complex, trans,trans,trans-[Pt(N3 )2 (OH)(succ)(py)2 ] (succ=succinylate, py=pyridine), has been conjugated to guanidinoneomycin to study the effect of this guanidinum-rich compound on the photoactivation, intracellular accumulation and phototoxicity of the pro-drug. Surprisingly, trifluoroacetic acid treatment causes the replacement of an azido ligand and the axial hydroxide ligand by trifluoroacetate, as shown by NMR spectroscopy, MS and X-ray crystallography. Photoactivation of the platinum-guanidinoneomycin conjugate in the presence of 5'-guanosine monophosphate (5'-GMP) led to the formation of trans-[Pt(N3 )(py)2 (5'-GMP)](+) , as does the parent platinum(IV) complex. Binding of the platinum(II) photoproduct {PtN3 (py)2 }(+) to guanine nucleobases in a short single-stranded oligonucleotide was also observed. Finally, cellular uptake studies showed that guanidinoneomycin conjugation improved the intracellular accumulation of the platinum(IV) pro-drug in two cancer cell lines, particularly in SK-MEL-28 cells. Notably, the higher phototoxicity of the conjugate in SK-MEL-28 cells than in DU-145 cells suggests a degree of selectivity towards the malignant melanoma cell line.

    Original languageEnglish
    Pages (from-to)18474-18486
    Number of pages13
    JournalChemistry: a European Journal
    Volume21
    Issue number50
    Early online date2 Nov 2015
    DOIs
    Publication statusPublished - 7 Dec 2015

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    Keywords

    • Antineoplastic Agents
    • Cell Line, Tumor
    • Guanidine
    • Humans
    • Ligands
    • Organoplatinum Compounds
    • RNA

    Cite this

    Shaili, E., Fernández-Giménez, M., Rodríguez-Astor, S., Gandioso, A., Sandín, L., García-Vélez, C., Massaguer, A., Clarkson, G. J., Woods, J. A., Sadler, P. J., & Marchán, V. (2015). A Photoactivatable Platinum(IV) Anticancer Complex Conjugated to the RNA Ligand Guanidinoneomycin. Chemistry: a European Journal, 21(50), 18474-18486. https://doi.org/10.1002/chem.201502373